San Francisco, CA (UroToday.com) Enzalutamide is an androgen-axis targeted therapy with established efficacy in the treatment of advanced prostate cancer (PCa), including metastatic castration-resistant PCa (mCRPC) and non-metastatic CRPC (nmCRPC).

TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, preventing DNA damage repair (DDR), and causing cell death in BRCA1/2-mutated cells. TALA is approved in the US to treat germline BRCA1/2-mutated HER2- locally advanced/metastatic breast cancer. It has a dual cytotoxic mechanism highlight below:

Prior studies have demonstrated the potential benefit of PARP inhibitors in the treatment of advanced prostate cancer, particularly in men with DNA repair defects.1 Indeed, work by Clarke et al.2 has previously established the efficacy of combination therapy of a PARP-inhibitor with abiraterone acetate in this same population of men.

PARP1 activity has been shown to support AR function, suggesting that co-blockade may synergize with AR directed therapy

In this study, Dr. Agarwal and colleagues examine the combination of TALA with ENZA in mCRPC, with the expectations that it may improve clinical outcomes, based on the strength of prior studies. Herein, they describe their proposed 2-part trial.

Eligibility criteria for both parts of the trial are as follows:

Men aged ≥18 years

Have asymptomatic/mildly symptomatic mCRPC

ECOG PS ≤1

No brain metastases

Have not received taxanes/novel hormonal therapy (NHT)

Inclusion and Exclusion criteria are summarized below:

The first phase of the trial (P1) is an open-label study to confirm the starting dose of TALA to be given in combination with ENZA. Phase 2 (P2) is a randomized double-blind study that will evaluate the safety, efficacy and patient-reported outcomes of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA in 2 cohorts (C).

The full trial design is below:Randomization will be stratified by prior treatment with NHT for castration sensitive prostate cancer (CSPC) or prior treatment with taxane-based chemotherapy for CSPC (yes/no), and DDR mutation status (deficient vs. nondeficient/unknown).

In terms of outcomes, for the first phase, the primary endpoint is safety and the secondary endpoint is pharmacokinetics of TALA and ENZA. For phase 2, the primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria or death and evaluated separately in all comers (C1) and DDR-deficient (DDR-deficient pts from C1 and C2 combined, N = 380 pts) populations. The key secondary endpoint is overall survival.

Study endpoints are summarized below:

Efficacy and progression will be assessed by radiographic evaluation every 8 weeks up to week 25 and every 8-12 weeks thereafter. Phase 2 analysis for rPFS is powered at 90% and 85% using a 2-sided log-rank test with alpha of 0.025, respectively, in the all comers and DDR deficient populations.

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